The subject matter disclosed herein relates to T-cell receptor alpha (TCRα) locus control region (LCR)-derived gene regulatory cassettes. A locus control region (LCR) is defined by an ability to impart position-independent and high-level tissue-specific expression of a linked transgene. The LCR protects the transgene from certain effects that could silence the transgene if it integrates into inactive chromatin.
The T-cell receptor α (TCRα) gene is exclusively expressed in T-lineage cells. Pre-rearranged TCRα transgenes are expressed only T-cell-bearing tissues, such as thymus and spleen, but not in other organs, such as liver and heart. Even within T-cell-bearing tissues, current vectors used in T-cell gene therapy are not immune from silencing effects that halt the expression of the transgene. Nor are these vectors spatiotemporally specific in their production of the therapeutic transgene product. This limits this approach to vector transduction of terminally differentiated T-cells.
It would be advantageous to transduce stem cell populations with such vectors to produce an ever-renewable source of T-cells expressing the therapeutic gene product. But to do this in a safe way, vectors must be designed to direct high-level therapeutic gene expression to T-cells, and not other stem cell progeny. To do this in an effective way, the vector mast also be equipped with regulatory DNA that enables the vector to be resilient to the silencing effects of heterochromatin dynamics during T-cell differentiation from stem cell precursors. Unfortunately, no vectors are currently known that are entirely satisfactory. A new vector is therefore desired.
The discussion above is merely provided for general background information and is not intended to be used as an aid in determining the scope of the claimed subject matter.